Method of treating bone with a curable composition

ABSTRACT

The present invention relates to a biocompatible polymer composition suitable for bone repair and a method of treating bone repair using a curable polymer composition wherein the cured composition has an elongation until rupture of at least 10%.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/751,002filed Jan. 2, 2004 now U.S. Pat. No. 7,670,622 which claims the benefitof EP patent application number 03075001.2 filed Jan. 2, 2003, both ofwhich are hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to a biocompatible polymer composition, suitablefor in vivo vessel repair, e.g. for repairing an aortic aneurysm.

BACKGROUND

Aneurysms are local dilatations in blood vessels, in particular arteriesthat gradually enlarge in time. Unless an aneurysm is adequatelytreated, it may eventually rupture and cause severe damage to the body,possibly even result in shock or death. Aortic aneurysms are inparticular an important cause of death in human adults of 55 years andolder.

Traditional repair of an aneurysm entails a major operation with anincision into the aneurysm, evacuation of the clot that is usuallycontained within, placement of a synthetic graft and wrapping of thegraft with the remnants of the artery wall.

A more recent development is the endovascular stent technique. Thisprocedure does not require general anaesthesia and can be done lessinvasively by simply placing a self-expanding stent via a catheterpassed through one of the femoral arteries into the aneurysm tostabilise it. Less fit patients are able to withstand the procedure,hospital stay is cut to 1 to 2 days, and post-operative recovery isshortened considerably.

In WO 95/08289 it is proposed to repair cardiovascular anomalies via theintroduction of a photo-activatable biopolymer, which is introduced tothe anomaly via a catheter system, after which the polymer iscross-linked. The publication mentions several examples of potentiallysuitable polymers, wherein it is suggested to be advantageous that thepolymers are not only photo-activatable but also biodegradable andresorbable.

A catheter system for delivering fluid materials, such as medicaments toa body vessel is reported in EP 0 667 131 A2. The fluid material is forexample a mixture comprising an epoxy resin that cures in the presenceof ions.

WO 96/182427 relates to an in situ stent forming catheter for deliveringdrugs and other fluid materials to an isolated area of a human vessel.As examples of fluid materials, mixtures comprising moisture curingpolymeric materials are mentioned, such as cyanoacrylate,polymethylacrylate, polylactic acid and polyglycolic acid.

The American U.S. Pat. No. 6,306,177 describes a method and a relatedcomposition for repairing tissue, in particular bone and cartilage. Themethod involves the use of a curable polyurethane. The publicationdescribes curable polyurethane compositions in general terms and issilent about specific characteristics of a composition for use in(aortic) aneurism repair, such as the viscosity requirements incombination with specific required or desired physical features of thecured compositions, inside the blood vessel.

The Dutch patent 1 005 190 discloses an apparatus for treating a bodycavity or body vessel with a curable material, such as polyurethane(PUR). It is described that the apparatus can be used in the treatmentof an aorta aneurysm.

Although considerable attention has been paid to the development ofdelivery systems for fluid material to a body cavity or vessel, it hasbeen found that the availability of compositions for treating cavitiesor vessels in vivo, in particular for repairing an aneurysm, is highlyunsatisfactory.

In particular, it has been found that known polymer compositions sufferfrom one or more drawbacks, e.g. known compositions have been found toshow unsatisfactory handling characteristics, unfavourable curingbehaviour, a relatively high level of toxicity, too lowbiocompatibility, too high thrombogenicity and/or insufficientdurability in vivo.

SUMMARY

Accordingly, it is an object of the present invention to provide a novelpolymer composition that can be used for treatment of cavity or vessel,in particular for the repair of an aneurysm that can be used as analternative to known compositions.

It has been found that this object is achieved by a specific fluidbiocompatible polymer composition having a viscosity in a specificrange. Accordingly, the present invention relates to a fluidbiocompatible polymer composition, suitable for vessel repair—inparticular for aneurysm repair—said composition comprising a matrixpre-polymer, a filler and a curing agent, wherein said composition has aviscosity at 25° C., as measured by a Brookfield viscosimeter, UK, of 2000-12 000 cSt (corresponding to 2-12 Pa·s for a composition with adensity of 1 000 kg/m³), which polymer is curable in an aqueousenvironment at a temperature of 37° C. It has been found that such apolymer on the one hand, has a satisfactory flowability to allow asufficiently swift administration to an aneurysm and on the other hand,allows sufficiently fast curing into a fixed structure to avoid too longdisconnection of the blood recirculation during an aneurysm repair.

Moreover, it has been found that satisfactory curing is achieved withoutexcessive heat release.

Such a composition has been found to have particularly favourablehandling characteristics. The composition has a suitable flowability toallow introduction of the composition at a site to be repaired in situthrough a narrow catheter (e.g. with an inner diameter of approximately1-1.2 mm and a length of about 50-60 cm length) in a sufficiently shorttime, typically within 1-2 min. Further, it has been found that duringapplication, the composition does not leak out of the application systemused to introduce the composition in situ (e.g. at a connection betweenpump and catheter) if a contrast medium is used for introducing andposition the catheter in place. As a contrast medium e.g. a water basedX-rays contrast fluid, such as Omnipaque® (e.g. at a concentration of300 mg iodine/ml), may be used.

It has further been found that this object is achieved by a fluidbiocompatible polymer composition having particular mechanicalproperties. Accordingly, the present invention relates to a fluidbiocompatible polymer composition, suitable for aneurysm repair,comprising a matrix pre-polymer, a filler and a curing agent whichbiocompatible polymer composition is curable in the presence of a curingcatalyst at 25° C. to form a cured material with an elongation untilrupture of at least 5% and/or an elastic modulus of at least 1 MPa. Ithas been found that such a composition is capable of repairing ananeurysm and also contributes positively to the prevention of furtherdilatation of the vessel at the site of the repaired aneurysm.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the present inventionwill be more fully understood from the following detailed description ofillustrative embodiments taken in conjunction with the accompanyingdrawings in which:

FIG. 1 schematically depicts an aneurysm in the aorta.

FIG. 2 graphically depicts the effect of the percent of added silicafiller on the overall mechanical properties such as stress and strain.

FIG. 3 graphically depicts a stress strain curve of silicone 0% silica,silicone with 20% vinyl Q® and 7% silica, silicone with 30% Vinyl Q®,silicone with 34% vinylQ®, silicone 34% Vinyl Q® and 4% silica with 1%microfibres, silicone with 34% vinyl Q® and 4% silica, and silicone with35% vinyl Q® and 5% silica.

FIGS. 4A-4G schematically depict how a bone may be provided with thecurable composition described herein.

DETAILED DESCRIPTION

In particular, the present invention relates to a biocompatible polymercomposition, suitable for treating a blood vessel, in particular foraneurysm repair, comprising a matrix pre-polymer, a filler and a curingagent, wherein said composition has a viscosity at 25° C., as measuredby Brookfield viscosimeter of 2 000 to 12 000 cSt, which biocompatiblepolymer composition is curable in the presence of a curing catalyst at37° C. to form a cured material with an elongation until rupture of atleast 5% and an elastic modulus of at least 1 MPa.

It has been found that a composition according to the invention showsvery favourable handling properties before application to a body vesselor cavity. It allows mixing with optionally added other ingredients,e.g. as indicated below, adequate application in a fluid state to thesite that is to be repaired (such as an aneurysm) in an acceptabletime-frame to avoid inclusion of anomalies—such as air bubbles—in thecomposition. Accordingly, a composition according to the invention ispreferably essentially free of a gas phase.

It has been found that upon curing of a composition according to theinvention, the resulting material has a very good durability in that itis capable of maintaining satisfactory mechanical properties and itsintegrity for a prolonged time, even up to or exceeding a patient'slifetime.

It has been found that a composition according to the invention iscapable of curing in vivo into a material having a sufficiently highstrength to function as an arterial graft.

A composition according to the invention that has been cured has beenfound to have a highly satisfactory resistance to abrasion whenimplemented in an artery.

The viscosity as defined herein is the kinematic viscosity in cSt asmeasured by Brookfield viscosimeter (UK), model ND J-1 and/or rheometerRMS 800 from Rheometrics, USA. The kinematic viscosity of a fluid in cStcorresponds to the dynamic viscosity in mPa·s divided by the density ofthe fluid in g/cm³.

The elongation until rupture is defined herein is the value as measuredby a Zwick 1445 tensile strength tester (Germany).

The elastic modulus as defined herein is the value as measured bydynamic mechanical analyser, DMA 7 from Perkin-Elmer (USA).

Preferably, the viscosity of the biocompatible polymer composition is inthe range of 3 000 to 10 000 cSt, more preferably 4 000 to 8 000 cSt.Particularly good results have been achieved with a composition having aviscosity of approximately 5 000 to 7 000 cSt. Such a polymercomposition is found to have particular satisfactory mechanicalproperties (after curing), in combination with sufficient flowability(before curing).

After curing, the elongation until rupture of the cured composition ispreferably at least 10%, more preferably at least 25% even morepreferably at least 50%. The upper limit is in practice not particularlyimportant. Very good results have for example been reached with a curedcomposition having an elongation until rupture of 500% or less, more inparticular of 250% or less.

The elastic modulus is preferably at least 2 MPa, more preferably atleast 3 MPa, even more preferably at least 4 MPa.

The upper limit is not particularly critical. Very good results havebeen achieved with a composition having an elastic modulus of less than20 MPa, after curing.

It has been found that a composition giving rise to a elastic modulus ofabout 5-15 MPa, is particularly advantageous with respect to thedurability of the cured material under in vivo aortic conditions.

Preferably, after curing of the composition the resulting material has astress value of at least 5 kPa at 1% strain, more preferably of at least30 kPa at 20% strain, even more preferably a stress value of at least 1MPa at 50% strain (As determined with Zwick 1445 or with DMA 7,Perkin-Elmer).

The glass transition temperature (Tg) of a cured material obtained froma composition according to the invention is typically less than 37° C.Preferably the Tg is less than 25° C. Very good results have beenachieved with a material having a Tg of less than −25° C. (Tg is thevalue as measured by differential scanning calorimetry (DSC) on a DSC 7,Perkin-Elmer.

The composition is preferably chosen such that the absolute value of thecuring enthalpy of the biocompatible polymer composition is less than 10J/g, as measured by determining the heat production during curing by DSC(DSC 7, Perkin-Elmer).

The components of a composition according to the invention can beprepared by mixing the component in a common mixing device. Particularlysuitable is a high shear mixer or an ultrasonic mixer. Suitable mixingconditions can be routinely determined by the skilled person based uponcommon general knowledge and the information disclosed herein. Verysuitable is for example an intermittent mixing procedure (e.g. at 20 000to 30 000 rpm for a 100 ml composition), wherein between periods ofmixing (e.g. of 1-20 min) the composition is allowed to rest in order tocool down (e.g. for 1 to 10 min).

The components or the composition itself should preferably be sterile orsterilisable. At least when present in the composition, the componentsshould have a sufficient hemocompatibility, when used in a blood vesseland are preferably non-thrombogenic and non-tumorogenic.

The term matrix pre-polymer is used herein to describe a curablemonomer, a curable oligomer or a curable polymer. Before curing thematrix pre-polymer typically comprises one or more functional groupsthat allow further polymerisation, e.g. by cross-linking, to form thematrix of the composition after it has been cured. It is stressed thatthe terms pre-polymer and polymer are to be interpreted broadly, withrespect to the number of monomeric units.

The number of monomeric units or molecular weight of the matrixpre-polymer is not particularly critical, as long as it provides asuitable viscosity in the composition. Good results have been obtainedwith a matrix pre-polymer having at least 1, preferably at least 5, morepreferably at least 20 monomeric units, before curing is initiated. Forpractical reasons, the matrix-polymer generally comprises less than 20000 monomeric units, preferably less than 1 000, more preferably lessthan 100, before curing is initiated.

Very good results have been achieved with a composition comprising amatrix pre-polymer having 1 to 5 monomeric units.

The number average molecular weight of the matrix pre-polymer may forexample be in the range of 500 to 400 000 gram/mol, preferably in therange of 6 000 to 280 000 gram/mol. As a matrix pre-polymer, anybiocompatible pre-polymer can be used that is curable underphysiological conditions into a material with satisfactory mechanicalproperties and that can be delivered to the site inside the body whereit is to cure.

The amount of matrix prepolymer can be chosen within wide limits,depending upon the desired viscosity and other properties and may beadequately determined by the skilled professional. Preferably theconcentration of the matrix pre-polymer is 10 to 85 wt. % based on thetotal weight of the composition, more preferably the concentration is inthe range of 50 to 75 wt. %. Very good results have been achieved with acomposition having an amount of matrix pre-polymer in the range of 60 to70 wt. %. Examples of suitable matrix pre-polymers are silicon(pre-)polymers, polyurethanes, and combinations thereof such as blends,hybrid polymers and copolymers comprising silicon (pre-)polymers and/orpolyurethanes.

Particular suitable hybrid polymers are polymers filled with a molecularsilica. A particular preferred molecular silica in a hybrid polymer is apolyhedral oligomeric silsesquioxane (P.O.S.S.). Such a molecular silicais commercially available from Hybrid Plastics, USA under the trademarkPOSS™.

Preferably the pre-polymer reacts essentially without forming arest-product, such as a gas (e.g. CO₂) or another residual product. Suchrest products may be detrimental to the properties, in particularphysical properties, of the cured composition.

A preferred matrix pre-polymer is a silicon (pre-)polymer, which is anexample of a pre-polymer that usually reacts without forming a restproduct. It has been found that a composition comprising a silicon(pre-)polymer is not only very suitable for repairing an aneurysm insuch a way that the repaired blood vessel has very satisfactorymechanical properties for a prolonged period of time, but that such a(pre-)polymer in a composition according to the invention also offersthe advantages of being hemocompatible, non-thrombogenic, highlybiocompatible and non-carcinogenic.

Further it has been found that a composition comprising a silicon(pre-)polymer is capable of curing fast, typically within 5 min. orless—preferably within 2-3 min or less—without generating excessive heatthat may do damage to the body or may give rise to defects in the curedmaterial. Further a composition comprising a silicon (pre-)polymer hasbeen found to be particularly suitable to prevent further dilatation ofa vessel, e.g. of an aorta at the site of a repaired aneurysm.

It has been found that a composition comprising a silicon (pre-) polymeris very suitable to repair an aneurism. The durability of the curedmaterial has been found to be very high. Life-times of 10-40 years ormore are considered to be feasible (based upon stretch test in an invitro simulation, simulating heart function at 60 beats per minute).

Preferably a silicon (pre-)polymer used in a composition according tothe invention has a start viscosity (i.e. before mixing it to acomposition according to the invention) of at least 300 cSt. Morepreferably the start viscosity is in the range of 300 to 1 500 cSt.

Highly preferred is a polydialkylsiloxane polymer, comprising at leasttwo vinyl groups, preferably at the terminal ends. Very good resultshave been achieved with a polydialkylsiloxane polymer having 3-5 vinylgroups.

Very good results have been achieved with a polydimethylsiloxanemonopolymer or a polydialkylsiloxane copolymer—e.g. a block copolymer, arandom copolymer or an alternating copolymer—mainly comprisingdimethylsiloxane units. A highly preferred polydimethylsiloxane polymeris shown in formula 1

Preferably the number average weight in case this polymer is used ischosen in the range of 20 000 to 200 000 g/mol.

A silicon (pre-)polymer is in practice preferred over polyurethanes, inparticular when used for aneurism repair. It has been found that in acomposition wherein the matrix pre-polymer is a polyurethanepre-polymer, the heat generation tends to be quite large. Further theCO₂ formed during the polymerisation may adversely affect physicalproperties such as the elongation up to rupture, the elastic modulus andthe durability.

Curing can be achieved in many ways, e.g. by the presence of a curingagent and/or by irradiation, in particular irradiation with UV light.The use of UV-light may for example be suitable in case of a localrepair. In practice, generally no exposure to radiation is required.

Preferably curing occurs by the presence of a curing agent. The use of acuring agent is particularly preferred. A curing agent as defined hereinis any agent that can react with the matrix pre-polymer to result in asolidification (e.g. by cross-linking or gelling) of the composition.Curing agents include cross-linking agents and agents that cure thecomposition in any other way. Preferably the curing agent is across-linking agent. The curing agents can be chosen from the group ofcuring agents that are suitable to react with the chosen matrixpre-polymer.

A suitable amount of curing agent can easily be determined, dependingupon the type of curing agent and the quantity and nature of the othercomponents in the composition. Preferably, the curing agent is presentin an amount of at least 0.1 wt. % based on the total weight of thecomposition, more preferably at least 5 wt. %. The amount of curingagent is preferably less than 15 wt. %, more preferably less than 10 wt.%.

Preferably the curing agent is present in the composition in an amountproviding a number of functional groups in the range of 1-10 times thenumber of functional groups that is provided by the matrix pre-polymer.

Functional groups, as used herein, are those functional groups that arecapable of participating in the curing, in particular by being capableof reacting with a functional group of another molecule (curing agent ormatrix pre-polymer) in the composition. Examples of functional groupsare vinyl groups, acryloyl groups, methacryloyl groups and hydridegroups. Vinyl groups are in particular preferred in the matrixpre-polymer. Hydride groups are in particular preferred in the curingagent.

Examples of suitable curing agents are polyalkylhydrosiloxane polymers,including fluorinated polyalkylhydrosiloxane polymers, functionalisedmolecular silica compounds, such as Vinyl Q® and P.O.S.S. compounds.Very good results, in particular in combination with a silicon(pre-)polymer as a matrix pre-polymer, have been achieved with apolyalkylhydrosiloxane polymer. When used in combination with a silicon(pre-)polymer as a matrix pre-polymer, the molar ratio of hydride tovinyl functional groups is preferably 1:1 to 10:1.

A preferred polyalkylhydrosiloxane polymer as a curing agent is acopolymer of alkylhydrosiloxane moieties and dialkylsiloxane moieties,preferably of methylhydrosiloxane moieties and dimethylsiloxanemoieties.

Preferably the amount of dialkylsiloxane moieties—in particulardimethylsiloxane moieties—and/or the amount of alkylhydrosiloxanemoieties—in particular methylhydrosiloxane moieties—in apolyalkylhydrosiloxane polymer is 1-100, and more preferably 5 to 20.The dialkylsiloxane-alkylhydrosiloxane copolymer may be a random,alternating or block copolymer.

As a filler any physiologically acceptable filler can be used. Thefiller may for example by essentially spherical, filament-like,disc-like or an agglomerate of smaller nanofiller particles.

In practice, the number average particle diameter of the fillers is inthe range of 10 to 50 000 nm, preferably in the range of 10-1000 nm,more preferably in the range of 10 to 500 nm

Very good results have been achieved with a nano-particle filler whichhave a relatively high specific area (characterised by a highBET-value), typically in the range of 50 to 400 m²/g., in particularwith hybrid-nanofillers i.e. a filler that not only acts as a filler,but that also contains reactive sites, e.g. vinyl groups, that arecapable of participating in the curing of the composition. Ahybrid-nanofiller has not only been found to have a positive effect onthe mechanical properties after curing, but is also found that thesehybrid fillers do not lead to adverse physiological reactions, or atleast are less prone to lead to adverse physiological reactions incomparison to several ordinary fillers.

It is also possible to use a combination of different fillers. It hasfor example been found that a combination of a hybrid-nanofiller, inparticular a silica based hybrid-nanofiller, in combination with ahydrophobic filler, in particular a silica hydrophobic filler.

The amount of filler in the composition depends inter alia on the typeof filler, its contribution to the viscosity of the composition. Alsothe desired characteristics of the composition after curing may play arole in determining the concentration. The skilled professional willreadily be able to determine a suitable concentration. Typically thefiller is present in an amount of at least 1 wt. %, based on the totalweight. The upper limit is essentially determined by the amount of otherconstituents, present in the composition. For practical reasons, theamount of filler is usually less than 50 wt. %, based upon the totalweight of the composition. Preferably the concentration is at least 2wt. %, more preferably at least 15 wt. %. The amount of filler ispreferably less than about 45 wt. %, more preferably less than about 40wt. %. Very good results have been achieved with a filler concentrationof 25 to 45 wt. %.

Examples of suitable fillers are fillers selected from the groupconsisting of silica, clay, mica, calcium carbonate, fibre glass,polyethylene-naphthalate and combinations thereof, which may be presentin unmodified or chemically modified form. Preferred is a nano-sizedsilica filler, e.g. a molecular silica filler. It has been found thatsilica not only contributes particular well to mechanical properties,but also is suitable as a contrast agent, e.g. for X-ray monitoring.

Preferably, the surface of the filler is hydrophobic, e.g. due tochemical modification. The term hydrophobic filler is used herein todescribe a filler, of which the surface has been treated with anon-polar compound that dissolves better (i.e. has a higher solubility)in an organic solvent such as an alkane than in water.

It has been found that such a filler contributes very satisfactorily tothe mechanical properties of the composition after curing and also hasonly a relatively small effect on the flowability in comparison tohydrophilic fillers.

A preferred hydrophobic filler is a filler, more preferably a silicafiller, wherein at least the surface has been modified with anorganosilicon compound, e.g. with dichlorodimethylsilane ((CH₃)₂SiCl₂),hexamethyl-disilazane ([(CH₃)₃Si]₂NH) or reactive polydimethylsiloxanes.Such fillers are readily available in the market, e.g. Aerosil R8200(Degussa), functionalised molecular silica (e.g. Vinyl Q® (Gelest,USA)). Besides the excellent mechanical properties of a cured material,obtained from a composition comprising a surface modified silica filler,it has been found that such a filler may also serve as a contrast agentas an alternative to commonly used separate contrast agents, or to beused in combination with (reduced concentration of) such a contrastagent.

Very good results have been realised with a filler modified withvinylalkylsiloxane, in particular a filler modified withvinyldimethylsiloxane. A cured material based upon a compositioncomprising vinylalkylsiloxane modified filler has been found to haveparticularly good mechanical properties and durability, afterimplementation in the body, in particular in combination with a silicon(pre-)polymer as a matrix pre-polymer and/or a alkylhydrosiloxane as acuring agent. Besides good mechanical properties for a prolonged period,it has been found that such a composition has a very advantageous lighttransparency and curing behaviour.

A composition according to the invention may essentially consist ofmatrix pre-polymer, curing agent and filler. A composition may compriseone or more additives, e.g. one or more additives selected from thegroup consisting of contrast agents, curing inhibitors and chainextenders.

As indicated above, in particular silica may be present not only as afiller but also as a contrasting agent. Other examples of particularlysuitable contrast agents include iodine based contrast agents(containing iohexyl e.g. Omnipaque®, (supplied by Nycomed). An iodinebased contrast agent (such as Omnipaque®) is a preferred contrast agent,in that it has been found that it does not adversely affect the curingprocess.

A chain extender may be present in a composition to change theelasticity modulus and/or the elongation until rupture of a curedmaterial with. Suitable examples of chain extenders include hydrideterminated polydimethyl siloxanes.

Very good results have been obtained with a chain extender, present in acomposition according to the invention in a concentration of 1-10 wt. %based upon the combined weight of filler, matrix pre-polymer and curingagent.

Curing inhibitors may be present in the composition to improve stabilityof the composition until the curing is induced, shortly beforeapplication of the composition. An examples of a curing inhibitors is1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane.

The curing may be initiated and propagated in any way suitable to curethe particular combination of matrix pre-polymer and curing agent aslong as this curing is physiological acceptable. The curing may forexample be started under influence of radiation, e.g. electromagneticradiation or chemically, e.g. by an added catalyst or reactant or by acomponent that is naturally present in the body, e.g. water orparticular ions.

Preferably the curing is performed under influence of a curing catalyst.The curing catalyst may for example be present in a compositioncomprising a matrix pre-polymer, a filler and/or other additives. Inparticular if such a curing catalyst composition comprises a matrixpre-polymer, it will usually be essentially free of curing agent.

It has been found that by using a curing catalyst, a cured material isobtained that has very favourable mechanical properties throughout thematerial.

Very good results have been achieved with a platinum catalyst, inparticular for curing a composition comprising a matrix pre-polymer withvinyl units as reactive site and a curing agent with hydride units asactive site.

Highly preferred examples of platinum catalysts are platinum complexes,in particular platinum complexes selected from the group consisting ofplatinum-divinyltetramethyldisiloxane complexes. Good results have interalia been realised when using such a complex in a concentration of 2 to7 ppm Pt based upon the total weight of the composition.

The concentration of curing catalyst can readily be determined dependingupon the composition and the desired curing time. For example for curinga composition comprising a silicon (pre-)polymer, in particular apolydialkylsiloxane polymer comprising at least two vinyl groups, and apolyalkylhydrosiloxane polymer, good results have been achieved with aplatinum catalyst in a concentration of at least 5 ppm (based upon thetotal weight of the biocompatible polymer composition). Particularfavourable with respect to the curing time has been found to be aconcentration of about 5 to 500 ppm.

The curing catalyst is preferably mixed with the composition, shortlybefore applying the composition to the body vessel or cavity. Very goodresults have been achieved by mixing a composition comprising a curingcatalyst with a biocompatible polymer composition according to theinvention in a static mixer, in particular in a static mixer comprisingat least 30 mixing elements. Static mixers are readily available in themarket. They comprise an elongated channel wherein for example amulti-helical screw is placed along which the fluids are passed andmixed. Herein each winding of the screw is considered as a single mixingelement.

The present invention further relates to the use of a biocompatiblepolymer composition according to the invention or a curing catalystcomposition to the invention, in the manufacture of a pharmaceuticallyacceptable composition for the treatment, in particular the in vivorepair, of an aneurysm and to the use of such composition in themanufacture of a physiologically acceptable composition for securing astent or stent-graft in an artery.

The present invention further relates to a kit of parts for use in an invivo aneurysm repair, comprising a biocompatible polymer compositionaccording to the invention, and a curing-catalyst composition.

Preferably the curing catalyst composition in a kit according to theinvention comprises at least one component selected from the groupconsisting of matrix pre-polymers, fillers and contrast agents.

Very good results have been realised with a kit, wherein the viscosityof the curing catalyst composition is at most 1 500 cSt higher or lowerthan the viscosity of the biocompatible polymer composition.

A particularly preferred kit comprises a biocompatible polymercomposition and a curing-catalyst composition in amounts in viscositiessuch that the mixture of biocompatible polymer composition and acuring-catalyst composition has a viscosity of 2 000-12 000 cSt at 25°C.

Much preferred is a kit, wherein the biocompatible polymer compositionmixed with the curing catalyst composition, has a curing time of 5 minor less, more preferably 2 to 3 min.

For typical applications the amount of biocompatible polymer compositionand curing agent composition is such that their total weight when mixedis 20 to 500 grams.

As indicated above, a composition according to the invention is suitablefor treating a body cavity or vessel. A composition according to theinvention is in particular suitable for forming a stent in situ inside abody vessel, more in particular for repairing an aneurysm in an artery,e.g. the aorta. The polymer composition can be introduced at the sitethat is to be treated by any delivering system suitable for deliveringfluid compositions in a body. Examples of such delivering systems andmethods of applying the composition are readily known in the art, e.g.from the publications mentioned herein, e.g. Dutch patent 1 005 190.

Accordingly, the present invention also relates to a method of treatinga body cavity or body vessel—preferably an aneurysm in a blood-vessel,with a composition according to the present invention, said methodcomprising the steps of covering the inner wall of the vessel or cavitywith an essentially cylindrical layer of the composition and curing thecomposition. Obviously the curing by and large takes place aftercovering the inner wall, although it is possible that the curing isinitiated shortly (typically up to about 1-10 min) before applying thecomposition to the wall.

In an embodiment, the composition is applied to the inner wall by usingan apparatus comprising a catheter with at the distal end an expandable,essentially cylindrical carrier, which carrier is inserted in the vesselor cavity, wherein the composition is applied between the outer wall ofthe carrier and the inner wall of the vessel or cavity, wherein thecarrier is expanded and has—in expanded state—at least one, preferablytwo rounded shoulders, at a distance from one another, which shouldersare in contact with the cavity or vessel wall, such that a filling spacefor the composition is formed between the two shoulders, the outer wallof the carrier and the inner wall of the vessel or cavity, and whereinthis filling space is provided with the composition. The composition canfor example be applied to the filling space via one or more holes in thecarrier.

A preferred example of a carrier is a balloon that is expansible underinfluence of pressure, e.g. transferred via a liquid or a gas. Theballoon is brought to the site to be treated, e.g. the aneurysm, whereit is expanded. Via a catheter, the composition is then injected intothe space between balloon and vessel wall. FIG. 1 shows an example of ananeurysm in the aorta. The arteries 1 are temporarily blocked from bloodcirculation with the help of three balloon catheters 2. As shown in thisfigure each of the balloons has one rounded shoulder 2 a. One cathetercomprises an echo sounder 4 to locate the renal arteries 1 a and 1 b.The biocompatible polymer composition—mixed with a curing catalystcomposition is injected via another catheter or a needle that has alsobeen introduced at the aneurysm via an artery.

The invention further relates to the treatment of a bone with a curablepolymer composition.

It has been found that a human or an invertebrate in general may beeffectively treated with a curable polymer composition in order toreduce the risk of complications of a future bone fracture.

The bone treated in accordance with this aspect of the invention ispreferably a collarbone or a hip.

Typically the (non-broken) bone is provided with a curable polymercomposition. Suitable compositions are known in the art, e.g. asdescribed herein or in one of the references cited in the presentdescription.

Preferably the curable polymer composition is a composition as describedin the present claims and/or description, although other composition maysuitably be employed.

In accordance with a method for treating a bone, a cavity is made in thebone, which may be done by a method generally known in the art, e.g. ina way known to introduce osteosynthetic material into a bone. Thereafterthe cavity is provided with the curable composition and the compositionis cured. FIG. 4 schematically shows by means of an example how a bonemay be provided with the curable composition. FIG. 4A shows how a drill2 is directed at a bone 1 and used to drill a hole (FIGS. 4B and 4C).Removal of the drill 2 provides a cavity 3 in the bone (FIG. 4D) that isfilled with the curable composition 5 (FIG. 4E), which is subsequentlyallowed to cure. If—at a later moment—the bone is fractured (FIG. 4F;arrows F indicate where forces are applied), the cured composition keepsthe fractured bone parts 1 a and 1 b in place, or at least reducesshifting of the bone parts (FIG. 4G).

The cavity is preferably provided along at least a substantial part ofthe bone, for instance by drilling, and filled with the curablecomposition, after which the composition is cured. The cured compositionthus preferably forms an elastic rod-like structure.

If the bone breaks after the composition is cured, the cured compositionmaintains or swiftly brings back the broken parts essentially in theright position, thus avoiding or at least reducing the risk ofcomplications due to shifting of the bone parts.

Such a method may for instance very suitably be carried out incombination with a surgery that has to be performed on a patient for anacute reason, for instance on a patient of which one of the hips or oneof the collarbones has been broken.

Accordingly, the invention also relates to the use of a curable polymercompositions in the manufacture of a physiologically acceptablecomposition for prophylactic treatment of a bone, preferably a hip or acollarbone. Such prophylactic treatment helps to avoid or at leastreduces the risk of complications after fracture.

The invention is further illustrated by the following examples

Example 1

Polydimethyldiloxane (PDMS) vinyl terminated oligomers (supplied byGelest, USA) were mixed with various weight percent of filler (Vinyl Q®)(supplied by Gelest, USA) in the range 0 to 50% w/w and with differenthydride methyl siloxane (hydride HMS-301™, supplied by ABCR, Germany.concentrations as well as different platinum concentrations, Theplatinum compound was platinum-divinyltetramethyldisiloxane complex,3-3.5% platinum concentration in vinylterminated ploydimethylsiloxane,supplied by ABCR, Germany.

The formulations providing the best viscosity and mechanical propertiesfollowing the protocol are obtained at a weight percent above 25% ofvinyl Q® in 1000 cSt PDMS vinyl terminated. The viscosity of theformulation containing 20% w/w Vinyl Q® in 1000 cSt PDMS vinylterminated oligomer was found to be 4 000 cSt.

The addition of 5% Aerosil R8200™ (supplied by Degussa, Germany) to the20% w/w Vinyl Q®, was found to accelerate the cure rate, increase themechanical properties. The viscosity increase varied from nosignificantly increase in the start viscosity up to an acceptableincrease from 4 000 to 5 000 cSt.

The 50% w/w Vinyl Q® in 1 000 cSt PDMS vinyl terminated provided aviscosity of 7 000 cSt.

Example 2

The following basic formulation was made:

-   -   20% w/w vinyl Q® (molecular filler)    -   70% w/w 1000 cSt PDMS vinyl terminated    -   10% w/w silica Aerosil R8200™

The composition was prepared as follows: The vinyl Q® was added to thePDMS. After gently mixing until a homogenous mixture was formed thesilica Aerosil R8200™ was added in small quantities at a time to 200 gof PDMS/Vinyl Q®, and was vigorously mixed with a Kinematica high shearmixer (Kinematica PT-MR 3000 EU/502) for one hour at 25 000 rpm. Theresulting mixture was homogenous.

From the resulting basic formulation of PDMS/vinyl Q®/silica twocomponents (A and B) were prepared. Component A contained 6 g hydridehaving 10 functional (HMS-301) in 24 g of PDMS/vinyl Q®/silica, andcomponent B contained 2.4 g platinum from a 0.0286% complex platinum (asin Example 1) added to 26 g PDMS/vinyl Q®/silica. The material was curedat to form sheets of 10 cm×10 cm×2 mm. It was found that the chainextender influenced the cured material, by reducing the tensile modulusand increasing the maximum elongation.

In a tensile strain test, a sample of the cured material was strained at60% from its original length and subjected to 100% stretch at 1260cycles per minute. The sample was tested for a life time equivalent toat least 10 years of stretching in vivo (heart rate 60 BPM). Theproperties still were satisfactory at the end of the test.

Example 3

The following basic formulation was made as indicated in Example 2

-   -   30% Vinyl Q® w/w    -   67% 1000 cSt PDMS vinyl terminated    -   3% w/w silica Aerosil R8200™

The component A contained 7 g HMS-301™ (9% of the total formulationweight), plus 23 g of the basic 30% w/w Vinyl Q® formulation givenabove, while component B contained 3 g platinum at 0.0286% complexplatinum in PDMS 1000 cSt plus 27 g from the basic formulation (with 30%Vinyl Q®).

A cylindrical test sample was produced by mixing component A & B andcuring the composition. Curing was performed at room temperature toproduce sheets as indicated in Example 2. In addition, a cylindricalaneurysm-type of shape was produced to fit the material to be tested inlong term experiments. The cylindrical test sample was connected to anair pressure at 0.5 bar, inflating each 0.3 seconds for two monthsbefore stopping the experiment. The sample did not show any signs offatigue or deterioration.

Example 4

Four samples (with a total weight of 60 grams) were produced based on1000 cSt PDMS vinyl terminated, each having the same fillerconcentration of 35.5 wt. % of Vinyl Q®, 5 wt. % silica from AerosilR8200™, each having the same platinum concentration 0.2 g at 3 wt. %complex platinum in PDMS 1 000 cSt., but having different hydrideconcentration (HMS-301™).

The HMS-301™ quantities per 60 g sample were as follows:

Example 4.1: 6.0 gr. HMS-301™

Example 4.2: 6.5 gr. HMS-301™

Example 4.3: 7.0 gr. HMS-301™

Example 4.5: 7.5 gr. HMS-301™

Cured samples (as indicated in Example 3) were connected to an airpressure of 0.5 bar, inflating each 0.3 seconds. After 4 months oftesting, the sample did not show any signs of fatigue or deterioration.

Example 4.2 showed the best results with respect to Young' modulus,elongation and tear resistance.

Example 5

The following basic formulation was made

-   -   49 wt. % Vinyl Q®    -   1.1 wt. % silica from Aerosil R8200™    -   49.9 wt % 1000 cSt PDMS vinyl terminated

As component A, a mixture was made containing 11 g HMS and 19 g from the49% w/w vinyl Q® basic formulation, and component B containing 0.4 grplatinum at 3% complex platinum in PDMS 1000 cSt and 29.6 gr from thesame basic Vinyl Q® formulation.

It was found that a cured test sample produced with this composition wasmore rigid than any of the samples made in Examples 1-4 or a test samplemade with clay or mica as nanofiller.

A cylindrical test sample was connected to an air pressure of 0.5 bar,inflating each 0.3 seconds. After 4 months of testing, the sample didnot show any signs of fatigue or deterioration.

Example 6

The modulus of cured silicone compositions, to be used as aorta implantwere measured using the Dynamic Mechanical Analyser (DMA 7 from PerkinElmer), in the stress-strain mode. The strength until sample rupture wasdetermined from samples which were hold between air-pressurised gripswithin the Zwick 1445. The mechanical properties were observed to bereproducible within an error of 5%. The effect of the percent of addedsilica filler on the overall mechanical properties such as stress andstrain are shown in FIG. 2. The elastic modulus of a cured compositionis determined by the initial slope of the corresponding curve.

There was a huge stress difference between a silicone system containing0% silica and that containing 12.5%. The static strain was notsignificantly different between the different samples until 200%stretching.

Also, no appreciable difference in stress existed in between siliconesystems having 12.5% and those having 20% silica.

The silicone/silica systems having 20% silica showed the highest tearstrength.

Example 7

The stress strain curve of the following systems was determined:silicone 0% silica, silicone with 20% vinyl Q® and 7% silica, siliconewith 30% Vinyl Q®, silicone with 34% vinylQ®, silicone 34% Vinyl Q® and4% silica with 1% microfibres, silicone with 34% vinyl Q® and 4% silica,and silicone with 35% vinyl Q® and 5% silica. Otherwise the conditionswere as indicated in the previous Examples.

The results are shown in FIG. 3.

Example 8

The Vinyl Q®/PDMS/silica nanofiller formulations of examples 1-7 wereput in glass pots and were brought to 200° C. for 15 minutes. No effectof temperature on the pre-polymerisation and/or crosslinks was noticed,which demonstrates that a silicon (pre-)polymer based compositionaccording to the invention can easily be sterilized.

1. A method for treating a bone comprising the steps of: making a cavityin the bone; providing the cavity with a curable polymer composition;and curing the composition to form a cured composition, wherein thecured composition has an elongation until rupture of at least 10%. 2.The method according to claim 1, wherein the cured composition has anelongation until rupture of at least 25%.
 3. The method according toclaim 2, wherein the cured composition has an elongation until ruptureof at least 50%.
 4. The method according to claim 1, wherein the curedcomposition has an elastic modulus of at least 2 MPa.
 5. The methodaccording to claim 1, wherein the curable polymer composition includes acuring agent.
 6. The method according to claim 1, wherein the step ofcuring the composition is initiated and propagated by radiation.
 7. Themethod according to claim 1, wherein the curable polymer compositionincludes a curing catalyst.
 8. The method according to claim 7, whereinthe curing catalyst is a platinum catalyst.
 9. The method according toclaim 1, comprising the step of mixing a curing catalyst with thecurable polymer composition in a static mixer, and thereafter providingthe cavity with the mixture.
 10. The method according to claim 1,wherein the bone is a hip or a collar bone.
 11. The method according toclaim 1, wherein the curable polymer composition comprises a matrixpre-polymer, a curing agent and an additive.
 12. The method according toclaim 11, wherein the additive is one or more members selected from thegroup consisting of fillers, contrast agents, curing inhibitors andchain extenders.
 13. The method according to claim 1, wherein the curedcomposition forms an elastic rod-like structure.
 14. The methodaccording to claim 1, wherein the curable polymer composition isbiocompatible and includes a matrix pre-polymer, a filler and a curingagent, wherein said biocompatible polymer composition is curable in thepresence of a curing catalyst at 37° C. to form the cured compositionhaving an elongation until rupture of at least 10% and an elasticmodulus of at least 1 MPa.
 15. The method according to claim 1, whereinthe curable polymer composition includes a silicon (pre-)polymer.